BACKGROUND: Long-term exposure to high levels of arsenic is associated with increased risk for cardiovascular disease, whereas risk from long-term exposure to low to moderate arsenic levels (< 100μg/L in drinking water) is unclear.OBJECTIVE: To evaluate the association between long-term exposure to low to moderate arsenic levels and incident cardiovascular disease.DESIGN: Prospective cohort study.SETTING: The Strong Heart Study baseline visit between 1989 and 1991, with follow-up through 2008.PATIENTS: 3575 American Indian men and women aged 45 to 74 years living in Arizona, Oklahoma, and North and South Dakota.MEASUREMENTS: The sum of inorganic and methylated arsenic species in urine at baseline was used as a biomarker of long-term arsenic exposure. Outcomes were incident fatal and nonfatal cardiovascular disease.RESULTS: A total of 1184 participants developed fatal and nonfatal cardiovascular disease. When the highest and lowest quartiles of arsenic concentrations (> 15.7 vs. < 5.8 μg/g creatinine) were compared,the hazard ratios for cardiovascular disease, coronary heart disease, and stroke mortality after adjustment for sociodemographic factors, smoking, body mass index, and lipid levels were 1.65 (95%CI, 1.20 to 2.27; P for trend < 0.001), 1.71 (CI, 1.19 to 2.44; P for trend < 0.001), and 3.03 (CI, 1.08 to 8.50; P for trend = 0.061),respectively. The corresponding hazard ratios for incident cardiovascular disease, coronary heart disease, and stroke were 1.32 (CI,1.09 to 1.59; P for trend = 0.002), 1.30 (CI, 1.04 to 1.62; P for trend = 0.006), and 1.47 (CI, 0.97 to 2.21; P for trend = 0.032).These associations varied by study region and were attenuated after further adjustment for diabetes, hypertension, and kidney disease measures.LIMITATION: Direct measurement of individual arsenic levels in drinking water was unavailable.CONCLUSION: Long-term exposure to low to moderate arsenic levels was associated with cardiovascular disease incidence and mortality.